Genetic Variant NM_174951.3:c.515G>A (chrX-8795394-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_174951.3(FAM9A):c.515G>A(p.Arg172Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000817 in 1,198,951 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 42 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000086 ( 0 hom. 42 hem. )

Consequence

FAM9A
NM_174951.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0750

Publications

2 publications found

Variant links:

Genes affected

FAM9A (HGNC:18403): (family with sequence similarity 9 member A) This gene is a member of a gene family which arose through duplication on the X chromosome. The encoded protein may be a nuclear protein that is localized to the nucleolus, and has some similarity to a synaptonemal complex protein. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Aug 2011]

FAM9A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07008353).

BS2

High Hemizygotes in GnomAdExome4 at 42 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174951.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM9A	NM_174951.3	MANE Select	c.515G>A	p.Arg172Gln	missense	Exon 7 of 10	NP_777611.1	Q8IZU1
	FAM9A	NM_001171186.1		c.515G>A	p.Arg172Gln	missense	Exon 7 of 10	NP_001164657.1	Q8IZU1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM9A	ENST00000381003.7	TSL:1 MANE Select	c.515G>A	p.Arg172Gln	missense	Exon 7 of 10	ENSP00000370391.3	Q8IZU1
	FAM9A	ENST00000543214.1	TSL:1	c.515G>A	p.Arg172Gln	missense	Exon 7 of 10	ENSP00000440163.1	Q8IZU1

Frequencies

GnomAD3 genomes

AF:

0.0000449

AC:

AN:

111457

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000940

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000226

AC:

AN:

176747

AF XY:

0.0000318

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000512

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000855

AC:

AN:

1087494

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

355404

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26136

American (AMR)

AF:

0.00

AC:

AN:

34819

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19158

East Asian (EAS)

AF:

0.00

AC:

AN:

29983

South Asian (SAS)

AF:

0.00

AC:

AN:

53304

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40351

Middle Eastern (MID)

AF:

0.000341

AC:

AN:

2929

European-Non Finnish (NFE)

AF:

0.000104

AC:

AN:

835267

Other (OTH)

AF:

0.000110

AC:

AN:

45547

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000449

AC:

AN:

111457

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33663

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30627

American (AMR)

AF:

0.00

AC:

AN:

10380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3574

South Asian (SAS)

AF:

0.00

AC:

AN:

2661

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5963

Middle Eastern (MID)

AF:

0.00

AC:

AN:

235

European-Non Finnish (NFE)

AF:

0.0000940

AC:

AN:

53195

Other (OTH)

AF:

0.00

AC:

AN:

1490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.0

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.0082

FATHMM_MKL

Benign

0.0037

LIST_S2

Benign

0.73

M_CAP

Benign

0.0014

MetaRNN

Benign

0.070

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.35

PhyloP100

-0.075

PROVEAN

Benign

0.69

REVEL

Benign

0.026

Sift

Benign

0.36

Sift4G

Benign

0.53

Polyphen

0.29

Vest4

0.085

MutPred

0.24

Loss of MoRF binding (P = 0.1167)

MVP

0.21

MPC

0.28

ClinPred

0.070

GERP RS

-1.2

Varity_R

0.080

gMVP

0.0075

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over